JP5544553B2 - Process for producing pyripyropene derivative and its intermediate - Google Patents

Description

Reference to related applications

  This patent application is accompanied by a priority claim based on Japanese Patent Application No. 2007-210804 (application date: August 13, 2007) which is a previously filed Japanese patent application. The entire disclosure of this earlier patent application is hereby incorporated by reference.

Background of the Invention

TECHNICAL FIELD The present invention relates to a method for producing a pyripyropene derivative useful as a pest control agent, and more specifically, a method for producing a pyripyropene derivative having acyloxy groups at positions 1 and 11 and a hydroxyl group at position 7. It is about.

BACKGROUND ART A pyripyropene derivative having an acyloxy group at the 1st and 11th positions and a hydroxyl group at the 7th position is a compound having a controlling effect against pests as described in WO2006 / 129714.

  As a method for producing a pyripyropene derivative having an acyloxy group at the 1-position and the 11-position and a hydroxyl group at the 7-position, WO2006 / 129714 and JP-A-8-2559569 are prepared using 1,7,11-triacyloxy derivatives as raw materials. A method for purifying or isolating from a plurality of products resulting from hydrolysis of a non-selective acyloxy group is disclosed. However, this method has a low yield and has a problem that it cannot be applied to mass synthesis.

  Japanese Patent Application Laid-Open No. 8-259569 describes the use of a protecting group in combination with the synthesis of a pyripyropene derivative. Journal of Antibiotics 49 11 11 11996, Bioorganic Medicinal Chemistry Letter 5 22 On page 2683, 1995, JP-A-8-269065 and WO2008 / 013336 disclose synthesis examples in which an acyl group is introduced at the 7-position using a protecting group. However, a specific method using a protecting group for the production of a pyripyropene derivative having an acyloxy group at the 1-position and the 11-position and a hydroxyl group at the 7-position is not disclosed.

Summary of the Invention

  From the pyripyropene A substance obtained as a natural product by using an appropriate protecting group (Japanese Patent Application Laid-Open No. 8-25969; Bioorganic Medicinal Chemistry Letter 5, Vol. 22, page 2683, 1995; WO 2004/060065). It has been found that a pyripyropene derivative in which the 1st and 11th positions are acyloxy groups and the 7th position is a hydroxyl group can be produced in high yield. The present invention is based on this finding.

  Accordingly, an object of the present invention is to provide a method for producing a pyripyropene derivative useful as a pest control agent, and a compound which is an intermediate for the production.

［式中、Ｒ’は、直鎖、分岐鎖、または環状のＣ_２−６アルキルカルボニル基（この基のアルキル部分が分岐鎖または環状であるときは、Ｃ_３−６アルキルカルボニル基）を表す］
で表される化合物Ｃを製造する方法が提供され、該方法は、
（ａ_１） 次式Ａ１：

［式中、Ａｃは、アセチル基を表す］
で表される化合物Ａ１の７位アセチル基を、塩基を用いて加水分解することにより選択的に脱アシル化した後、７位の水酸基を保護することによって、次式Ｂ１：

［式中、
Ａｃは、上記で定義したとおりであり、
Ｒ_１ａは、置換されていてもよい直鎖Ｃ_２−４アルキルカルボニル基、ハロゲン原子で置換されていてもよい−ＳｉＲ_３Ｒ_４Ｒ_５基（ここで、Ｒ_３、Ｒ_４およびＲ_５は、互いに独立して、直鎖もしくは分岐鎖状のＣ_１−６アルキル基、またはフェニル基を表す）、ハロゲン原子で置換されていてもよいＣ_１−６アルキルオキシ−Ｃ_１−６アルキル基、ハロゲン原子で置換されていてもよいＣ_１−６アルキルチオ−Ｃ_１−６アルキル基、ハロゲン原子で置換されていてもよい直鎖、分岐鎖もしくは環状のＣ_１−４アルキル基（この基が分岐鎖または環状であるときは、Ｃ_３−４アルキル基）、ハロゲン原子で置換されていてもよいＣ_２−６アルケニル基、ハロゲン原子で置換されていてもよいＣ_２−６アルキニル基、置換されていてもよいベンジル基、または置換されていてもよい飽和もしくは不飽和の５もしくは６員の複素環基を表し、
ここで、Ｒ_１ａにおいて、アルキルカルボニル基が有してもよい置換基は、ハロゲン原子、Ｃ_１−４アルキルオキシ基、Ｃ_１−４ハロアルキルオキシ基、Ｃ_１−４アルキルカルボニル基、Ｃ_１−４ハロアルキルカルボニル基、Ｃ_１−４アルキルカルボニルオキシ基およびＣ_１−４ハロアルキルカルボニルオキシ基からなる群から選択されるものであり、複素環基およびベンジル基が有してもよい置換基は、ハロゲン原子、Ｃ_１−４アルキル基、Ｃ_１−４アルキルオキシ基、Ｃ_１−４ハロアルキルオキシ基、Ｃ_１−４アルキルチオ基、Ｃ_１−４ハロアルキル基、Ｃ_１−４アルキルカルボニル基、Ｃ_１−４ハロアルキルカルボニル基、Ｃ_１−４アルキルカルボニルオキシ基、Ｃ_１−４ハロアルキルカルボニルオキシ基、ニトロ基およびシアノ基からなる群から選択されるものである］
で表される化合物Ｂ１を得た後、化合物Ｂ１の１位および１１位のアセチル基を、塩基を用いて加水分解することにより脱アシル化することによって、次式Ｆａ：

［式中、Ｒ_１ａは、上記で定義したとおりである］
で表される化合物Ｆａを得る工程、または
（ａ_２） 化合物Ａ１または次式Ａ４’：

［式中、Ａ_１’、Ａ_７’およびＡ_１１’は、同一または異なっていてもよく、アセチル基またはプロピオニル基を表し、但し、Ａ_１’、Ａ_７’およびＡ_１１’が同時にアセチル基を表すことはない］
で表される化合物Ａ４’の１位、７位および１１位のアシル基を、塩基を用いて加水分解することにより脱アシル化した後、１位および１１位の水酸基を保護することによって、次式Ｄ：

［式中、２つのＲ_２は、互いに一緒になって、次式Ｄ−１、Ｄ−２、Ｄ−３およびＤ−４：

（式中、Ｙ_１は、水素原子またはＣ_１−４アルキル基を表し、Ｘは、同一または異なってもよく、水素原子、Ｃ_１−４アルコキシ基またはニトロ基を表し、ｎは０〜５を表す）から選択される基を表す］
で表される化合物Ｄを得た後、化合物Ｄの７位の水酸基を保護することにより、次式Ｅ：

［式中、
Ｒ_１ｂは、ホルミル基、置換されていてもよい直鎖Ｃ_１−４アルキルカルボニル基、置換されていてもよいベンジル基、ハロゲン原子で置換されていてもよい−ＳｉＲ_３Ｒ_４Ｒ_５基（ここで、Ｒ_３、Ｒ_４およびＲ_５は、互いに独立して、直鎖もしくは分岐鎖状のＣ_１−６アルキル基、またはフェニル基を表す）、ハロゲン原子で置換されていてもよいＣ_１−６アルキルオキシ−Ｃ_１−６アルキル基、ハロゲン原子で置換されていてもよいＣ_１−６アルキルチオ−Ｃ_１−６アルキル基、ハロゲン原子で置換されていてもよい直鎖、分岐鎖もしくは環状のＣ_１−４アルキル基（この基が分岐鎖または環状であるときは、Ｃ_３−４アルキル基）、ハロゲン原子で置換されていてもよいＣ_２−６アルケニル基、ハロゲン原子で置換されていてもよいＣ_２−６アルキニル基、または置換されていてもよい飽和もしくは不飽和の５もしくは６員の複素環基を表し、
ここで、Ｒ_１ｂにおいて、アルキルカルボニル基が有してもよい置換基は、ハロゲン原子、Ｃ_１−４アルキルオキシ基、Ｃ_１−４ハロアルキルオキシ基、Ｃ_１−４アルキルカルボニル基、Ｃ_１−４ハロアルキルカルボニル基、Ｃ_１−４アルキルカルボニルオキシ基およびＣ_１−４ハロアルキルカルボニルオキシ基からなる群から選択されるものであり、複素環基およびベンジル基が有してもよい置換基は、ハロゲン原子、Ｃ_１−４アルキル基、Ｃ_１−４アルキルオキシ基、Ｃ_１−４ハロアルキルオキシ基、Ｃ_１−４アルキルチオ基、Ｃ_１−４ハロアルキル基、Ｃ_１−４アルキルカルボニル基、Ｃ_１−４ハロアルキルカルボニル基、Ｃ_１−４アルキルカルボニルオキシ基、Ｃ_１−４ハロアルキルカルボニルオキシ基、ニトロ基およびシアノ基からなる群から選択されるものであり、
Ｒ_２は、上記で定義したとおりである］
で表される化合物Ｅを得て、さらに化合物Ｅにおける１位および１１位の保護基を脱保護することによって、次式Ｆｂ：

［式中、Ｒ_１ｂは、上記で定義したとおりである］
で表される化合物Ｆｂを得る工程、ならびに
（ｂ） 化合物ＦａまたはＦｂにおける１位および１１位の水酸基を目的とするＲ’に対応するアシル化剤でアシル化することによって、次式Ｂ２ａまたはＢ２ｂ：

［式中、Ｒ_１ａ、Ｒ_１ｂおよびＲ’は、上記で定義したとおりである］
で表される化合物Ｂ２ａまたは化合物Ｂ２ｂを得た後、化合物Ｂ２ａまたは化合物Ｂ２ｂの７位の保護基を脱保護する工程
を含んでなる。And according to the first aspect of the present invention, the following formula C:

[Wherein, R ′ represents a linear, branched, or cyclic C _2-6 alkylcarbonyl group (or a C _3-6 alkylcarbonyl group when the alkyl portion of this group is branched or cyclic). ]
A method for producing a compound C represented by the formula:
(A ₁ ) The following formula A1:

[In the formula, Ac represents an acetyl group]
The 7-position acetyl group of the compound A1 represented by formula (1) is selectively deacylated by hydrolysis using a base, and then the 7-position hydroxyl group is protected to give the following formula B1:

[Where:
Ac is as defined above,
R _1a is a linear C _2-4 alkylcarbonyl group which may be substituted, —SiR ₃ R ₄ R ₅ group which may be substituted with a halogen atom (where R ₃ , R ₄ and R ₅ are , independently of one another, a linear or branched _{C 1-6} alkyl group or a phenyl group), _{C 1-6} optionally substituted by a halogen atom alkyloxy _{-C 1-6} alkyl group, C _1-6 alkylthio-C _1-6 alkyl group optionally substituted with a halogen atom, linear, branched or cyclic C _1-4 alkyl group optionally substituted with a halogen atom (this group is branched) When it is a chain or a cyclic group, a C _3-4 alkyl group), a C _2-6 alkenyl group optionally substituted with a halogen atom, a C _2-6 alkynyl group optionally substituted with a halogen atom, substituted The Also represent a 5 or 6-membered heterocyclic group which may benzyl group or a saturated optionally substituted or unsaturated, and,
Here, in R _1a , the substituent that the alkylcarbonyl group may have is a halogen atom, a C _1-4 alkyloxy group, a C _1-4 haloalkyloxy group, a C _1-4 alkylcarbonyl group, a C _{1- A} substituent selected from the group consisting of a ₄ haloalkylcarbonyl group, a C _1-4 alkylcarbonyloxy group, and a C _1-4 haloalkylcarbonyloxy group, which the heterocyclic group and the benzyl group may have are halogen Atom, C _1-4 alkyl group, C _1-4 alkyloxy group, C _1-4 haloalkyloxy group, C _1-4 alkylthio group, C _1-4 haloalkyl group, C _1-4 alkylcarbonyl group, C _{1- 4} haloalkylcarbonyl groups, _C1-4 alkylcarbonyloxy groups, _C1-4 haloalkylcarbonyloxy groups, nitro groups and Is selected from the group consisting of cyano groups]
And then deacylating the acetyl groups at the 1-position and 11-position of the compound B1 with a base to give the following formula Fa:

[Wherein R _1a is as defined above]
Or (a ₂ ) Compound A1 or the following formula A4 ′:

[Wherein, A ₁ ′, A ₇ ′ and A ₁₁ ′ may be the same or different and each represents an acetyl group or a propionyl group, provided that A ₁ ′, A ₇ ′ and A ₁₁ ′ are acetyl groups at the same time. Does not represent]
The acyl groups at the 1-position, 7-position and 11-position of the compound A4 ′ represented by the following are deacylated by hydrolysis with a base, and then the hydroxyl groups at the 1-position and the 11-position are protected, Formula D:

[Wherein _two R ₂ , taken together, have the following formulas D-1, D-2, D-3 and D-4:

Wherein Y ₁ represents a hydrogen atom or a C _1-4 alkyl group, X may be the same or different, and represents a hydrogen atom, a C _1-4 alkoxy group or a nitro group, and n is 0 to 5 Represents a group selected from
Then, by protecting the hydroxyl group at the 7-position of compound D, the following formula E:

[Where:
R _1b is a formyl group, an optionally substituted linear C _1-4 alkylcarbonyl group, an optionally substituted benzyl group, an optionally substituted —SiR ₃ R ₄ R ₅ group ( Here, R ₃ , R ₄ and R ₅ each independently represent a linear or branched C _1-6 alkyl group or a phenyl group), C ₁ optionally substituted with a halogen atom _-6 alkyloxy-C _1-6 alkyl group, C _1-6 alkylthio-C _1-6 alkyl group optionally substituted with a halogen atom, straight chain, branched chain or cyclic optionally substituted with a halogen atom A C _1-4 alkyl group (when this group is branched or cyclic, a C _3-4 alkyl group), a C _2-6 alkenyl group optionally substituted with a halogen atom, or a halogen atom. An optionally substituted C _2-6 alkynyl group, or an optionally substituted saturated or unsaturated 5- or 6-membered heterocyclic group,
Here, in R _1b , the substituent that the alkylcarbonyl group may have is a halogen atom, a C _1-4 alkyloxy group, a C _1-4 haloalkyloxy group, a C _1-4 alkylcarbonyl group, a C _{1- A} substituent selected from the group consisting of a ₄ haloalkylcarbonyl group, a C _1-4 alkylcarbonyloxy group, and a C _1-4 haloalkylcarbonyloxy group, which the heterocyclic group and the benzyl group may have are halogen Atom, C _1-4 alkyl group, C _1-4 alkyloxy group, C _1-4 haloalkyloxy group, C _1-4 alkylthio group, C _1-4 haloalkyl group, C _1-4 alkylcarbonyl group, C _{1- 4} haloalkylcarbonyl groups, _C1-4 alkylcarbonyloxy groups, _C1-4 haloalkylcarbonyloxy groups, nitro groups and Is selected from the group consisting of cyano groups,
R ₂ is as defined above]
In addition, by deprotecting the 1-position and 11-position protecting groups in Compound E, the following formula Fb:

[Wherein R _1b is as defined above]
And (b) acylating the 1-position and 11-position hydroxyl groups in the compound Fa or Fb with an acylating agent corresponding to the target R ′, to obtain a compound Fb represented by the following formula B2a or B2b :

[Wherein R _1a , R _1b and R ′ are as defined above]
And a step of deprotecting the protecting group at the 7-position of compound B2a or compound B2b.

［式中、Ｒ_１ａは、上記で定義したとおりであり、Ｒ’は、環状のＣ_３−６アルキルカルボニル基を表す］
で表される化合物Ｂ２ａを製造する方法が提供され、該方法は、
前記化合物Ａ１の７位アセチル基を、塩基を用いて加水分解することにより選択的に脱アシル化した後、７位の水酸基を保護することによって、次式Ｂ１：

［式中、ＡｃおよびＲ_１ａは、上記で定義したとおりである］
で表される化合物Ｂ１を得た後、化合物Ｂ１の１位および１１位のアセチル基を、塩基を用いて加水分解することにより脱アシル化することによって、次式Ｆａ：

［式中、Ｒ_１ａは、上記で定義したとおりである］
で表される化合物Ｆａを得て、次に、化合物Ｆａにおける１位および１１位の水酸基を目的とするＲ’に対応するアシル化剤でアシル化することを含んでなる。According to a second aspect of the present invention, the following formula B2a:

[Wherein R _1a is as defined above, and R ′ represents a cyclic C _3-6 alkylcarbonyl group]
A method for producing a compound B2a represented by the formula:
The 7-position acetyl group of the compound A1 is selectively deacylated by hydrolysis with a base, and then the 7-position hydroxyl group is protected to give the following formula B1:

[Wherein Ac and R _1a are as defined above]
And then deacylating the acetyl groups at the 1-position and 11-position of the compound B1 with a base to give the following formula Fa:

[Wherein R _1a is as defined above]
And then acylating the hydroxyl groups at positions 1 and 11 in compound Fa with an acylating agent corresponding to the target R ′.

［式中、Ａ_１、Ａ_７およびＡ_１１は、同一または異なっていてもよく、アセチル基またはプロピオニル基を表す］
で表される化合物Ａ４の１位、７位および１１位のアシル基を、塩基を用いて加水分解することにより脱アシル化した後、１位および１１位の水酸基を保護することによって、前記化合物Ｄを得た後、化合物Ｄの７位の水酸基を保護することにより前記化合物Ｅを得て、さらに化合物Ｅにおける１位および１１位の保護基を脱保護することによって前記化合物Ｆｂを得て、次に、化合物Ｆｂにおける１位および１１位の水酸基をＲ’に対応するアシル化剤でアシル化することを含んでなる。According to a third aspect of the present invention, there is provided a method for producing the compound B2b (R ′ in formula B2b represents a cyclic C _3-6 alkylcarbonyl group), and the method comprises:
Formula A4:

[Wherein A ₁ , A ₇ and A ₁₁ may be the same or different and each represents an acetyl group or a propionyl group]
The acyl group at the 1-position, 7-position and 11-position of the compound A4 represented by the formula: After obtaining D, the compound E is obtained by protecting the hydroxyl group at the 7-position of the compound D, and the compound Fb is obtained by further deprotecting the 1- and 11-position protecting groups in the compound E. Next, the method comprises acylating the hydroxyl groups at the 1-position and the 11-position in the compound Fb with an acylating agent corresponding to R ′.

According to a fourth aspect of the present invention, there is provided a method for producing the compound C (wherein R ′ in formula C represents a cyclic C _3-6 alkylcarbonyl group), which method is the same as in the compound Fb. After obtaining the compound B2b by acylating the hydroxyl groups at the 1-position and the 11-position with an acylating agent corresponding to R ′, deprotecting the 7-position protecting group of the compound B2b.

  According to a fifth aspect of the present invention, there is provided a method for producing the compound C, wherein the method hydrolyzes the 1-position, 7-position and 11-position acyl groups of the compound A4 using a base. The compound D is obtained by protecting the hydroxyl groups at the 1-position and the 11-position after being deacylated, and then the compound E is obtained by protecting the hydroxyl group at the 7-position of the compound D. By deprotecting the 1- and 11-position protecting groups in the compound Fb, and then acylating the 1- and 11-position hydroxyl groups in the compound Fb with an acylating agent corresponding to R ′ After obtaining the compound B2b, the method comprises deprotecting the protecting group at the 7-position of the compound B2b.

［式中、Ｒ_１bは、上記で定義したとおりであり、Ｒ’は、環状のＣ_３−６アルキルカルボニル基を表す］
で表される。According to the sixth aspect of the present invention, there is provided a compound useful as an intermediate for producing a pyripyropene derivative having an acyloxy group at the 1-position and the 11-position and a hydroxyl group at the 7-position, the compound having the following formula B2b :

[Wherein, R _1b is as defined above, and R ′ represents a cyclic C _3-6 alkylcarbonyl group]
It is represented by

  According to the present invention, a pyripyropene derivative useful as a pest control agent having an acyloxy group at the 1-position and the 11-position and a hydroxyl group at the 7-position can be produced in high yield.

Detailed description of the invention

  In the present specification, “halogen” means fluorine, chlorine, bromine, or iodine.

  In this specification, the terms “alkyl,” “alkenyl,” or “alkynyl” as a substituent or part of a substituent, respectively, are straight chain, branched chain, cyclic, or their unless otherwise defined. Means a combination of alkyl, alkenyl or alkynyl.

In this specification, the symbol “C _ab ” attached to _a substituent means that the number of carbon atoms contained in the substituent is a to b. Furthermore, it means that the "C _a-b" in the case of "C _a-b alkylcarbonyl", excluding the carbon atom of the carbonyl moiety, the number of carbon atoms in the alkyl moiety is from a number to a number b To do.

  In this specification, the term “haloalkyl group” means an alkyl group substituted with at least one halogen atom. Similarly, the terms “haloalkyloxy group”, “haloalkylcarbonyl group” and “haloalkylcarbonyloxy group” refer to an alkyloxy group, an alkylcarbonyl group and an alkylcarbonyloxy group each substituted with at least one halogen atom. means.

Specific examples of the linear, branched or cyclic C _2-6 alkylcarbonyl group represented by R ′ (when the alkyl part of this group is branched or cyclic, a C _3-6 alkylcarbonyl group) include: A cyclopropanecarbonyl group, a propionyl group, etc. are mentioned. The alkylcarbonyl group is preferably a cyclic C _3-6 alkylcarbonyl group, and more preferably a cyclopropanecarbonyl group.

—SiR ₃ R ₄ R ₅ group represented by R _1a and R _1b (wherein R ₃ , R ₄ and R ₅ are each independently a linear or branched C _1-6 alkyl group, or phenyl Specific examples of (representing a group) include trimethylsilyl group, triethylsilyl group, triisopropylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group and the like. The -SiR ₃ R ₄ R ₅ group may be substituted, and examples of the substituent include a halogen atom. The -SiR ₃ R ₄ R ₅ group is preferably an alkylsilyl group in which all of R ₃ , R ₄ and R ₅ represent a linear or branched C _1-6 alkyl group, more preferably tert -A butyldimethylsilyl group.

Specific examples of the linear, branched or cyclic C _1-4 alkyl group represented by R _1a and R _1b (or a C _3-4 alkyl group when this group is branched or cyclic) include a methyl group , Ethyl group, propyl group, i-propyl group, cyclopropyl group, n-butyl group, i-butyl group, tert-butyl group and the like. This alkyl group may be substituted, and examples of the substituent include a halogen atom.

Specific examples of the C _2-6 alkenyl group represented by R _1a and R _1b include a vinyl group, (1- or 2-) propenyl group, (1-, 2- or 3-) butenyl group, (1-2) -, 3- or 4-) pentenyl group, (1-, 2-, 3-, 4- or 5-) hexenyl group and the like. This alkenyl group may be substituted, and examples of the substituent include a halogen atom.

Specific examples of the C _2-6 alkynyl group represented by R _1a and R _1b include an ethynyl group, a (1- or 2-) propynyl group, a (1-, 2- or 3-) butynyl group, (1--2 -, 3- or 4-) pentynyl group, (1-, 2-, 3-, 4- or 5-) hexynyl group and the like. This alkynyl group may be substituted, and examples of the substituent include a halogen atom.

Specific examples of the saturated or unsaturated 5- or 6-membered heterocyclic group represented by R _1a and R _1b include a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrofuranyl group, and a tetrahydrothiofuranyl group. It is done. This heterocyclic group may be substituted, and examples of the substituent include a halogen atom, a _C1-4 alkyl group, a _C1-4 alkyloxy group, a _C1-4 haloalkyloxy group, and a _C1-4 alkylthio group. C _1-4 haloalkyl group, C _1-4 alkylcarbonyl group, C _1-4 haloalkylcarbonyl group, C _1-4 alkylcarbonyloxy group, C _1-4 haloalkylcarbonyloxy group, nitro group and cyano group. . This heterocyclic group is preferably a tetrahydropyranyl group.

Specific examples of the linear C _2-4 alkylcarbonyl group represented by R _1a include a propionyl group, a propylcarbonyl group, and an n-butylcarbonyl group. The alkylcarbonyl group may be substituted, and examples of the substituent include a halogen atom, a _C1-4 alkyloxy group, a _C1-4 haloalkyloxy group, a _C1-4 alkylcarbonyl group, and a _C1-4 haloalkyl. Examples include a carbonyl group, a C _1-4 alkylcarbonyloxy group, and a C _1-4 haloalkylcarbonyloxy group.

Specific examples of the linear C _1-4 alkylcarbonyl group represented by R _1b include an acetyl group, a propionyl group, a propylcarbonyl group, and an n-butylcarbonyl group. The alkylcarbonyl group may be substituted, and examples of the substituent include a halogen atom, a _C1-4 alkyloxy group, a _C1-4 haloalkyloxy group, a _C1-4 alkylcarbonyl group, and a _C1-4 haloalkyl. Examples include a carbonyl group, a C _1-4 alkylcarbonyloxy group, and a C _1-4 haloalkylcarbonyloxy group.

The C _1-6 alkyloxy-C _1-6 alkyl group represented by R _1a and R _1b may be substituted, and examples of the substituent include a halogen atom.

The C _1-6 alkylthio-C _1-6 alkyl group represented by R _1a and R _1b may be substituted, and examples of the substituent include a halogen atom.

The benzyl group represented by R _1a and R _1b may be substituted. Examples of the substituent include a halogen atom, a C _1-4 alkyl group, a C _1-4 alkyloxy group, a C _1-4 haloalkyloxy group, C _1-4 alkylthio group, C _1-4 haloalkyl group, C _1-4 alkylcarbonyl group, C _1-4 haloalkylcarbonyl group, C _1-4 alkylcarbonyloxy group, C _1-4 haloalkylcarbonyloxy group, nitro group and A cyano group is mentioned.

R _1a is preferably a —SiR ₃ R ₄ R ₅ group which may be substituted with a halogen atom (wherein R ₃ , R ₄ and R ₅ are each independently a linear or branched C _{A 1-6} alkyl group or a phenyl group), or a saturated or unsaturated 5- or 6-membered heterocyclic group which may be substituted, more preferably a —SiR ₃ R ₄ R ₅ group (wherein , R ₃ , R ₄ and R ₅ each independently represent a linear or branched C _1-6 alkyl group or a phenyl group), or a saturated or unsaturated 5- or 6-membered heterocyclic ring More preferably -SiR ₃ R ₄ R ₅ group (wherein R ₃ , R ₄ and R ₅ are each independently a linear or branched C _1-6 alkyl group, or phenyl Group) or tetra It is a hydropyranyl group, most preferably a tert-butyldimethylsilyl group or a tetrahydropyranyl group.

R _1b is preferably an acetyl group, a chloroacetyl group, a saturated or unsaturated 5- or 6-membered heterocyclic group which may be substituted, or —SiR ₃ R ₄ R ₅ which may be substituted with a halogen atom. A group (wherein R ₃ , R ₄ and R ₅ each independently represents a linear or branched C _1-6 alkyl group or a phenyl group), more preferably an acetyl group, a chloro group, An acetyl group or a —SiR ₃ R ₄ R ₅ group optionally substituted with a halogen atom (wherein R ₃ , R ₄ and R ₅ are each independently a straight chain or branched C _{1- 6} represents an alkyl group or a phenyl group), more preferably an acetyl group, a chloroacetyl group or a tert-butyldimethylsilyl group, and most preferably an acetyl group or a chloroacetate group. It is assumed to be a til group.

（式中、Ｙ_１は、水素原子またはＣ_１−４アルキル基を表し、Ｘは、同一または異なってもよく、水素原子、Ｃ_１−４アルコキシ基またはニトロ基を表し、ｎは０〜５を表す）とされ、より好ましくはイソプロピリデン、ベンジリデンまたはｐ−メトキシベンジリデンとされる。他の実施態様によれば、２つのＲ₂が一緒になって表す置換基は、好ましくはＤ−１とされ、より好ましくはイソプロピリデンとされる。The substituent represented by two R _{2 taken} together is preferably the following formula D-1 or D-2:

Wherein Y ₁ represents a hydrogen atom or a C _1-4 alkyl group, X may be the same or different, and represents a hydrogen atom, a C _1-4 alkoxy group or a nitro group, and n is 0 to 5 More preferably isopropylidene, benzylidene or p-methoxybenzylidene. According to another embodiment, the substituent represented by the two R _{2 taken} together is preferably D-1, more preferably isopropylidene.

A ₁ , A ₇ and A ₁₁ are preferably both acetyl groups.

According to a preferred embodiment of the present invention, in the method according to the first aspect or the method according to the fifth aspect, R ′ is a cyclic C _3-6 alkylcarbonyl group.

According to another preferred embodiment of the present invention, in the method according to the first aspect, R _1a is a —SiR ₃ R ₄ R ₅ group optionally substituted with a halogen atom (where R ₃ , R ₄ And R ₅ each independently represent a linear or branched C _1-6 alkyl group or a phenyl group), or an optionally substituted saturated or unsaturated 5- or 6-membered heterocyclic ring Based on.

According to another preferred embodiment of the present invention, in the method according to the first aspect or the method according to the third aspect, R _1b may be substituted with an acetyl group, a chloroacetyl group or a halogen atom. ₃ R ₄ R ₅ group (wherein R ₃ , R ₄ and R ₅ independently of each other represent a linear or branched C _1-6 alkyl group or a phenyl group).

（式中、Ｙ_１は、水素原子またはＣ_１−４アルキル基を表し、Ｘは、同一または異なってもよく、水素原子、Ｃ_１−４アルコキシ基またはニトロ基を表し、ｎは０〜５を表す）
を表す。According to another preferred embodiment of the present invention, in the method according to the first aspect or the method according to the third aspect, two R ₂ , taken together, have the following formula D-1 or D-2:

Wherein Y ₁ represents a hydrogen atom or a C _1-4 alkyl group, X may be the same or different, and represents a hydrogen atom, a C _1-4 alkoxy group or a nitro group, and n is 0 to 5 Represents
Represents.

According to another preferred embodiment of the present invention, in the method according to the second aspect, R _1a is an optionally substituted linear C _2-4 alkylcarbonyl group, optionally substituted with a halogen atom— SiR ₃ R ₄ R ₅ group (wherein R ₃ , R ₄ and R ₅ independently of each other represent a linear or branched C _1-6 alkyl group or a phenyl group), or substituted It may be a saturated or unsaturated 5- or 6-membered heterocyclic group which may be present.

According to another preferred embodiment of the present invention, in the compound according to the sixth aspect, R _1b is an acetyl group, a chloroacetyl group, a —SiR ₃ R ₄ R ₅ group optionally substituted with a halogen atom (here R ₃ , R ₄ and R ₅ each independently represent a linear or branched C _1-6 alkyl group or a phenyl group), or an optionally substituted saturated or unsaturated group It is a 5- or 6-membered heterocyclic group, and R ′ is a cyclic C _3-6 alkylcarbonyl group.

  Yet another preferred embodiment of the present invention includes a method wherein R ′ in the formula B2a, formula B2b and formula C is a propionyl group or a cyclopropanecarbonyl group.

Yet another preferred embodiment is a method via the compound Fa, wherein R _1a in the formula B1, Fa, or B2a is an optionally substituted linear or branched alkylsilyl group, The method is a saturated or unsaturated 5- or 6-membered heterocyclic group which may be substituted.

Yet another preferred embodiment is a method via the compound Fb, wherein R _1b in the formula E, Fb or B2b is an acetyl group, a chloroacetyl group, or an optionally substituted straight chain or And a branched alkylsilyl group.
Yet another preferred embodiment is a method via the compound Fb, wherein R ₂ in the formula D or E is a group represented by the formula D-3.
A more preferred embodiment is a method via the compounds D, E, Fb and B2b, wherein R ₂ in the formula D or E is a group represented by the formula D-3, and the formula E, R _1b in Fb or B2b is an acetyl group, a chloroacetyl group, or an optionally substituted linear or branched alkylsilyl group, and R ′ in formula B2b and formula C is cyclopropanecarbonyl The method which is group is mentioned.

［式中、Ｒ’は、環状のＣ_３−６アルキルカルボニル基を表す］
で表される化合物Ｃを製造する方法が提供され、該方法は、次式Ａ４：

［式中、Ａ_１、Ａ_７、Ａ_１１は、同一または異なっていてもよく、アセチル基またはプロピオニル基を表す］
で表される化合物Ａ４の１位、７位および１１位のアシル基を、塩基を用いて加水分解することにより脱アシル化した後、１位および１１位の水酸基を保護することによって、次式Ｄ：

［式中、２つのＲ_２は、互いに一緒になって、次式Ｄ−１：

（式中、Ｙ_１は、水素原子またはＣ_１−４アルキル基を表す）で表される基を表す］
で表される化合物Ｄを得た後、化合物Ｄの７位水酸基を保護することにより、次式Ｅ：

［式中、Ｒ_１ｂは、アセチル基またはクロロアセチル基を表し、Ｒ_２は、上記で定義したとおりである］
で表される化合物Ｅを得て、さらに化合物Ｅにおける１位および１１位の保護基を脱保護することによって、次式Ｆｂ：

［式中、Ｒ_１ｂは、上記で定義したとおりである］
で表される化合物Ｆｂを得て、次に、化合物Ｆｂにおける１位および１１位の水酸基をＲ’に対応するアシル化剤でアシル化することによって、次式Ｂ２ｂ：

［式中、Ｒ_１ｂおよびＲ’は、上記で定義したとおりである］
で表される化合物Ｂ２ｂを得た後、化合物Ｂ２ｂの７位の保護基を脱保護することを含んでなる。According to a further preferred embodiment of the present invention,
Formula C:

[Wherein R ′ represents a cyclic C _3-6 alkylcarbonyl group]
A method for producing a compound C represented by the formula:

[Wherein A ₁ , A ₇ and A ₁₁ may be the same or different and each represents an acetyl group or a propionyl group]
The acyl groups at the 1-position, 7-position and 11-position of the compound A4 represented by the formula (1) are deacylated by hydrolysis with a base, and then the hydroxyl groups at the 1-position and the 11-position are protected, D:

[Wherein the _two R _{2 s} together form the following formula D-1:

(Wherein Y ₁ represents a hydrogen atom or a C _1-4 alkyl group)
And then protecting the 7-position hydroxyl group of compound D to give the following formula E:

[Wherein R _1b represents an acetyl group or a chloroacetyl group, and R ₂ is as defined above]
In addition, by deprotecting the 1-position and 11-position protecting groups in Compound E, the following formula Fb:

[Wherein R _1b is as defined above]
And then acylating the hydroxyl groups at the 1-position and the 11-position in the compound Fb with an acylating agent corresponding to R ′:

[Wherein R _1b and R ′ are as defined above]
And then deprotecting the protecting group at the 7-position of compound B2b.

  The present invention will be described in further detail along the following scheme.

In the above scheme, Ac, R _1a , R _1b , A ₁ , A ₇ , A ₁₁ , and R ₂ are as defined above, and R ′ is a linear, branched or cyclic C _2-6. Represents an alkylcarbonyl group (C _3-6 alkylcarbonyl group when the alkyl portion of this group is branched or cyclic).

  You may use the product in each process for the following process, without post-processing.

1-1: Production of Compound A3 from Compound A1 Compound A1 is described in, for example, JP-A-6-184158, WO2004 / 060065, JP-A-8-2559569, or Bioorganic Medicinal Chemistry Letter Vol. It can be obtained by the method described.

  Examples of the solvent used in the step of producing compound A3 from compound A1 include alcohol solvents having 1 to 4 carbon atoms such as methanol, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, N, N-dimethylformamide, Examples thereof include aprotic polar organic solvents such as dimethyl sulfoxide, N, N-dimethylacetamide and acetonitrile, halogen solvents such as dichloromethane and chloroform, or water, and mixed solvents thereof.

  Examples of the base used include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, Inorganic bases such as lithium hydroxide and barium hydroxide, alkali metals such as sodium methoxide, sodium ethoxide and potassium tert-butoxy, alkoxides of alkaline earth metals, 1,8-diazabicyclo [5.4.0] undeca Examples include organic bases such as 7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine, pyridine, hydrazine, guanidine, and preferably 1,8-diazabicyclo [5. 4.0] Undeca-7-D 1,5-diazabicyclo [4.3.0] non-5-ene, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, tert-butoxy potassium Particularly preferred are 1,8-diazabicyclo [5.4.0] undec-7-ene and tert-butoxypotassium.

  The amount of the base used is preferably 0.01 to 1.2 equivalents relative to compound A1. The reaction temperature is preferably in the range of −20 ° C. to 50 ° C. The reaction time is preferably in the range of 0.5 hours to 7 days.

1-2: In the step of producing the compound B1 from Compound A3 of Compound B1 from compound A3, protection of the 7-position hydroxyl group, _R 1a -Hal corresponding to _{R 1a} of interest (the Hal represents a halogen atom) R _1a halides, acid anhydrides, mixed acid anhydrides or 3,4-dihydropyran represented by the formula: in the presence of a base, in the presence or absence of an acid, or dicyclohexylcarbodiimide 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, carbonyldiimidazole, dipyridyl disulfide, diimidazoyl disulfide, 1,3,5-trichlorobenzoyl chloride, 1,3,5-trichlorobenzoyl anhydride , PyBop, PyBrop, and the like.

  This step can be carried out without solvent, but can also be carried out using a solvent. Solvents used include ketone solvents such as acetone and diethyl ketone, ether solvents such as diethyl ether, diisopropyl ether and tetrahydrofuran, ester solvents such as ethyl acetate and butyl acetate, N, N-dimethylformamide, N, N -Aprotic polar organic solvents such as dimethylacetamide, dimethylsulfoxide, acetonitrile, polar organic solvents such as pyridine, halogenated hydrocarbon solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as toluene, and mixed solvents thereof Is mentioned.

  Examples of the base used include sodium carbonate, potassium carbonate, sodium hydride, tert-butoxypotassium, sodium methoxide, sodium ethoxide, pyridine, dimethylaminopyridine, imidazole, 1,8-diazabicyclo [5.4.0] undeca. -7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine and the like.

  Examples of the acid used include p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, p-toluenesulfonic acid pyridinium salt, 10-camphorsulfonic acid, hydrochloric acid, sulfuric acid and the like.

  The reaction temperature is preferably in the range of −20 ° C. to 50 ° C. The reaction time is preferably in the range of 0.5 hours to 4 days.

1-3: Production of Compound Fa from Compound B1 As a solvent used in the step of producing Compound Fa from Compound B1, an alcohol solvent having 1 to 4 carbon atoms such as methanol, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane and the like Ether solvents, N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide, aprotic polar organic solvents such as acetonitrile, halogen solvents such as dichloromethane and chloroform, or water, and mixed solvents thereof Can be mentioned.

  Examples of the base used include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, Inorganic bases such as lithium hydroxide and barium hydroxide, alkali metals such as sodium methoxide, sodium ethoxide and potassium tert-butoxy, alkoxides of alkaline earth metals, 1,8-diazabicyclo [5.4.0] undeca Examples include organic bases such as 7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine, pyridine, hydrazine, guanidine, and preferably 1,8-diazabicyclo [5. 4.0] Undeca-7-D 1,5-diazabicyclo [4.3.0] non-5-ene, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, particularly preferably potassium carbonate Is done.

  The base is preferably used in an amount of 0.01 to 10 equivalents relative to Compound B1. The reaction temperature is preferably in the range of −20 ° C. to 50 ° C. The reaction time is preferably in the range of 0.5 to 48 hours.

2-1: Production of Compound A2 from Compound A4 As compound A4 and compound A4 ′, for example, natural products obtained by the methods described in JP-A-6-184158, WO94 / 09147, JP-A-8-239385, etc. Alternatively, for example, a derivative produced by the method described in JP-A-8-259569 can also be used.

  Solvents used in the step of producing compound A2 from compound A4 include alcohol solvents having 1 to 4 carbon atoms such as methanol, ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, N, N-dimethylformamide, Examples thereof include aprotic polar organic solvents such as dimethyl sulfoxide, N, N-dimethylacetamide and acetonitrile, halogen solvents such as dichloromethane and chloroform, or water, and mixed solvents thereof.

  Examples of the base used include sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, Inorganic bases such as lithium hydroxide and barium hydroxide, alkali metals such as sodium methoxide, sodium ethoxide and potassium tert-butoxy, alkoxides of alkaline earth metals, 1,8-diazabicyclo [5.4.0] undeca Examples include organic bases such as 7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine, pyridine, hydrazine, guanidine, and preferably 1,8-diazabicyclo [5. 4.0] Undeca-7-D 1,5-diazabicyclo [4.3.0] non-5-ene, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, particularly preferably potassium carbonate Is done.

  The amount of the base used is preferably 0.01 to 10 equivalents relative to Compound A4. The reaction temperature is preferably in the range of −20 ° C. to 50 ° C. The reaction time is preferably in the range of 0.5 to 48 hours.

According to this step, compound A2 is similarly produced from compound A1 or compound A4 ′ (compounds in which A ₁ , A ₇ and A ₁₁ in compound A4 are A ₁ ′, A ₇ ′ and A ₁₁ ′, respectively). Can do.

2-2: Production of Compound E via Compound D from Compound A2 Solvents used in the step of producing compound D from compound A2 include ketone solvents such as acetone and diethyl ketone, diethyl ether, diisopropyl ether, dioxane, Ether solvents such as tetrahydrofuran, ester solvents such as ethyl acetate and butyl acetate, aprotic polar organic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and acetonitrile, dichloromethane and chloroform Examples include halogenated hydrocarbon solvents, aromatic hydrocarbon solvents such as toluene, and mixed solvents thereof.

1-position and 11-position of the protection of hydroxyl group, dimethoxypropane, acetone, optionally substituted benzaldehyde or a dimethyl acetal thereof corresponding to R ₂ of interest, 2-methoxypropene, 2-ethoxy propene, phosgene, Triphosgene, trichloroacetyl chloride, p-nitrobenzyloxycarbonyl chloride, carbonyldiimidazole and the like can be used. P-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, p-toluenesulfonic acid pyridinium salt, 10-camphorsulfonic acid, hydrogen fluoride, hydrochloric acid, hydrogen bromide, sulfuric acid, iodine, iron chloride, chloride Acid catalysts such as tin, zinc chloride, aluminum chloride, trimethylchlorosilane, trimethylsilyl triflate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (preferably p-toluenesulfonic acid pyridinium salt and p-toluene (Sulphonic acid) is preferably used in an amount of 0.001 to 20 equivalents (more preferably 0.01 to 5 equivalents, more preferably 0.01 to 0.04 equivalents) relative to compound A2. .

  The reaction temperature is preferably in the range of −20 ° C. to 50 ° C., more preferably in the range of room temperature to 50 ° C. The reaction time is preferably in the range of 0.5 to 48 hours.

More specifically, for example, when obtaining compounds D and E in which R ₂ is D-1, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, p-toluenesulfonic acid pyridinium salt, 10-camphor An acid catalyst such as sulfonic acid is used in an amount of 0.001 to 20 equivalents, preferably 0.01 to 5 equivalents, more preferably 0.01 to 0.04 equivalents relative to Compound A2, and dimethoxy The compound A2 is reacted with a protecting group-introducing reagent such as propane, 2-methoxypropene, 2-ethoxypropene, or p-toluenesulfonic acid, p-toluenesulfonic acid pyridinium salt, sulfuric acid or copper sulfate in an acetone solvent. It can be used and reacted in an amount of 0.001 to 20 equivalents.

When compounds D and E in which R ₂ is D-2 are obtained, an acid catalyst such as p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, p-toluenesulfonic acid pyridinium salt, zinc chloride is used as the compound. It can be used in an amount of 0.001 to 20 equivalents relative to A2, and can be reacted with an optionally substituted benzaldehyde or its dimethylacetal.

  Next, although the process of manufacturing the compound E from the compound D can be implemented without a solvent, it can also be implemented using a solvent. Solvents used include ketone solvents such as acetone and diethyl ketone, ether solvents such as diethyl ether, diisopropyl ether, dioxane and tetrahydrofuran, ester solvents such as ethyl acetate and butyl acetate, N, N-dimethylformamide, dimethyl Aprotic polar organic solvents such as sulfoxide, N, N-dimethylacetamide, acetonitrile, polar organic solvents such as pyridine, halogenated hydrocarbon solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as toluene, and the like A mixed solvent is mentioned.

The introduction of protecting groups at the 7- hydroxyl groups corresponding to R _1b are _the halides of _{R 1b} represented by _{R 1b -Hal, R 1b OH,} R 1b Cl, (R 1b) 2 O, mixed anhydride, or 3,4-dihydropyran is used, in the presence of a base, in the presence or absence of an acid, or dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, It can be carried out by using a condensing agent such as imidazole, dipyridyl disulfide, diimidazoyl disulfide, 1,3,5-trichlorobenzoyl chloride, 1,3,5-trichlorobenzoyl anhydride, PyBop, PyBrop.

  Examples of the base used include sodium carbonate, potassium carbonate, sodium hydride, tert-butoxypotassium, sodium methoxide, sodium ethoxide, pyridine, dimethylaminopyridine, imidazole, 1,8-diazabicyclo [5.4.0] undeca. -7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine and the like.

  Examples of the acid used include p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, p-toluenesulfonic acid pyridinium salt, 10-camphorsulfonic acid, hydrochloric acid, sulfuric acid and the like.

  The reaction temperature is preferably in the range of −20 ° C. to 50 ° C. The reaction time is preferably in the range of 0.5 hours to 7 days.

More specifically, for example, when R _1b is a linear C _1-4 alkylcarbonyl group (for example, acetyl group, chloroacetyl group) optionally substituted with a halogen atom, it is solvent-free, tetrahydrofuran, dichloromethane , N, N-dimethylformamide or pyridine and a mixed solvent thereof, R _1b Cl or (R _1b ) ₂ O is used in an amount of 1 to 20 equivalents relative to Compound D, and pyridine, dimethylamino as a base Pyridine or triethylamine can be used in an amount of 0.1 to 20 equivalents relative to Compound D and reacted at −20 ° C. to 50 ° C.

R _1b may be substituted with a halogen atom —SiR ₃ R ₄ R ₅ group (wherein R ₃ , R ₄ and R ₅ are independently of each other linear or branched C _1-6 In the case of dichloromethane, chloroform, N, N-dimethylformamide, N, N-dimethylacetamide, or a mixed solvent thereof, the halide of R _1b with respect to compound D In an amount of 1 to 10 equivalents, and imidazole as a base can be used in an amount of 1 to 10 equivalents relative to Compound D and reacted at -20 ° C to 50 ° C.

2-3: Production of Compound Fb from Compound E As a solvent used in the step of producing Compound Fb from Compound E, alcohol solvents having 1 to 4 carbon atoms such as methanol, ketone solvents such as acetone and diethyl ketone, Ether solvents such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, aprotic polar organic solvents such as N, N-dimethylformamide, dimethyl sulfoxide, N, N-dimethylacetamide and acetonitrile, and halogen solvents such as dichloromethane and chloroform Or water and a mixed solvent thereof.

For deprotection of the R ₂ moiety, acetic acid, trifluoroacetic acid, trifluoroacetic anhydride, hydrogen fluoride, hydrochloric acid, hydrogen bromide, sulfuric acid, p-toluenesulfonic acid, p-toluene, depending on the type of protecting group Sulfonic acid monohydrate, p-toluenesulfonic acid pyridinium salt, organic acid such as 10-camphorsulfonic acid, or boron chloride, magnesium bromide, dinitrozinc, bismuth chloride, cerium chloride, iron chloride, tin chloride, zinc chloride Hydrogenation catalysts such as aluminum chloride, palladium carbon and palladium hydroxide can be used in an amount of 0.01 to 20 equivalents relative to Compound E.

  The reaction temperature is preferably in the range of −20 ° C. to 50 ° C. The reaction time is preferably in the range of 0.5 to 48 hours.

More specifically, for example, when R ₂ in compound E is D-1, hydrochloric acid in water, methanol, tetrahydrofuran, dichloromethane, chloroform, N, N-dimethylformamide, acetonitrile or acetic acid, or a mixed solvent thereof. , Acetic acid, p-toluenesulfonic acid, p-toluenesulfonic acid monohydrate, p-toluenesulfonic acid pyridinium salt, or dinitrozinc, bismuth chloride (preferably hydrochloric acid, acetic acid, p-toluenesulfonic acid pyridinium salt) Using the compound E in an amount of 0.01 to 20 equivalents, the compound Fb can be obtained by reacting at −20 ° C. to 50 ° C., preferably room temperature to 40 ° C.

When R ₂ is D-2, 10-camphorsulfonic acid is used in an amount of 0.01 to 20 equivalents relative to Compound E in water, methanol, tetrahydrofuran or chloroform, or a mixed solvent thereof. Then, the compound Fb can be obtained by reacting at −20 ° C. to 50 ° C., preferably at room temperature to 40 ° C.

3: Production of Compound B2a from Compound Fa and Production of Compound B2b from Compound Fb The step of producing Compound B2a from Compound Fa and the step of producing Compound B2b from Compound Fb can be carried out without solvent. It can also be carried out using a solvent. Solvents used include ketone solvents such as acetone and diethyl ketone, ether solvents such as diethyl ether, diisopropyl ether and tetrahydrofuran, ester solvents such as ethyl acetate and butyl acetate, N, N-dimethylformamide, N, N -Aprotic polar organic solvents such as dimethylacetamide, dimethylsulfoxide and acetonitrile, halogenated hydrocarbon solvents such as dichloromethane and chloroform, aromatic hydrocarbon solvents such as toluene, and mixed solvents thereof.

The introduction of the R ′ group at the 1-position and the 11-position is carried out using R′OH, R′Cl, (R ′) ₂ O, or a mixed acid anhydride corresponding to the target R ′ in the presence of a base. Or in the absence, or dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, carbonyldiimidazole, dipyridyl disulfide, diimidazolyl disulfide, 1,3,5-trichlorobenzoyl chloride, 1 , 3,5-trichlorobenzoyl anhydride, PyBop, PyBrop, and the like.

  As the base to be used, sodium carbonate, potassium carbonate, sodium hydride, tert-butoxy potassium, sodium methoxide, sodium ethoxide, pyridine, 4-dimethylaminopyridine, imidazole, 1,8-diazabicyclo [5.4.0] ] Undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine (preferably pyridine) and the like.

  The reaction temperature is preferably in the range of −20 ° C. to 50 ° C., more preferably in the range of 0 ° C. to 30 ° C. The reaction time is preferably in the range of 0.5 hours to 48 hours.

4: Production of Compound C from Compound B2a or Compound B2b As a solvent used in the step of producing Compound C from Compound B2a or Compound B2b, an alcohol solvent having 1 to 4 carbon atoms such as methanol, diethyl ether, diisopropyl ether, Ether solvents such as tetrahydrofuran and dioxane, aprotic polar organic solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide and acetonitrile, halogenated hydrocarbon solvents such as dichloromethane and chloroform, toluene and the like Aromatic hydrocarbon solvents, water and mixed solvents thereof.

Deprotection of R _1b in compound B2b can be carried out depending on the type of protecting group. For example, when R _1b is a formyl group, an acetyl group, or a chloroacetyl group, the base is sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, hydrogen Inorganic bases such as potassium halide, sodium cyanide, potassium cyanide, magnesium hydroxide, calcium hydroxide, lithium hydroxide and barium hydroxide, alkali metals such as sodium methoxide, sodium ethoxide and potassium tert-butoxy, alkaline earth metals Alkoxides, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, triethylamine, diisopropylethylamine, pyridine, hydrazine, guanidine, etc. Organic base (preferably Can be used in an amount of 0.01-10 equivalents, preferably 0.1-2 equivalents, relative to compound B2b. .

R _1b may be a C _1-6 alkyloxy-C _1-6 alkyl group optionally substituted with a halogen atom, a C _1-6 alkylthio-C _1-6 alkyl group optionally substituted with a halogen atom, a halogen atom A linear, branched or cyclic C _1-4 alkyl group which may be substituted with C _2-6 alkenyl group which may be substituted with a halogen atom, or C ₂ which may be substituted with a halogen atom _{A -6} alkynyl group or an optionally substituted saturated or unsaturated 5- or 6-membered heterocyclic ring, an optionally substituted benzyl group, or an optionally substituted -SiR ₃ R ₄ R If it is ₅ group, p- toluenesulfonic acid, p- toluenesulfonic acid monohydrate, p- toluenesulfonate pyridinium salt, hydrogen fluoride - pyridine, trifluoride Kamizu -Organic acids such as triethylamine, acetic acid, chloroacetic acid, trifluoroacetic acid, trifluoroacetic anhydride, hydrogen fluoride, hydrochloric acid, hydrogen bromide, sulfuric acid, thiophenol, 10-camphorsulfonic acid, or boron chloride, boron bromide , Magnesium bromide, cerium chloride, copper chloride, copper sulfate, lithium chloride, iron chloride, tin chloride, zinc chloride, zinc bromide, aluminum chloride, titanium chloride, palladium carbon, palladium hydroxide, palladium chloride, etc. , Trimethylchlorosilane, trimethyliodosilane, trimethylsilyl triflate, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, etc. are used in an amount of 0.1 to 10 equivalents relative to compound B2b. Can do.

  The reaction temperature is preferably in the range of −20 ° C. to 50 ° C., more preferably in the range of 0 ° C. to room temperature. The reaction time is preferably in the range of 0.5 hours to 7 days.

  According to this step, compound C can be similarly produced from compound B2a.

  Specific examples of the present invention are shown below, but the present invention is not limited thereto.

Example 1:
Synthesis of 7-deacetylpyripyropene A Pyripyropene A (30 mg) was dissolved in 80% aqueous methanol (2 mL), and 1,8-diazabicyclo [5.4.0] -undec-7-ene (9 mg) was added. And stirred at room temperature for 1.5 hours. Acetic acid was added to the reaction solution to stop the reaction, the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product of 7-deacetylpyripyropene A. This was purified by preparative thin-layer column chromatography (Merck silica gel 60F ₂₅₄ 0.5 mm, acetone: hexane = 1: 1) to obtain 7-deacetylpyripyropene A (17 mg, 61% yield). . From the measurement results of ESI-MS and ¹ H-NMR, it was confirmed that it was PR-7 described in JP-A-08-2559569.

Example 2:
Synthesis of 7-O-tert-butyldimethylsilyl-7-deacetylpyripyropene A 7-deacetylpyripyropene A (30 mg) synthesized by the method of Example 1 was added to N, N-dimethylformamide (5 mL). After dissolution, imidazole (113 mg) and tert-butyldimethylchlorosilane (250 mg) were added. After stirring at room temperature for 24 hours, the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give a crude product of 7-O-tert-butyldimethylsilyl-7-deacetylpyridopopenen A. (470 mg) was obtained.

ESI-MS: m / z 656 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 0.11 (3H, s), 0.16 (3H, s), 0.90 (3H, s), 0.96 (9H, s), 1.30-1.38 (1H, m), 1.32-1.37 (1H, m), 1.41 (3H, s), 1.60 (3H, s), 1.61-1.69 (2H, m), 1.77-1.92 (1H, m), 2.05 (6H, s), 2.15 (1H, m ), 2.89 (1H, d, J = 2.4 Hz), 3.64-3.70 (2H, m), 3.73 (1H, d, J = 11.6 Hz), 3.83 (1H, d, J = 11.6 Hz), 4.78 (1H , dd, J = 4.8, 11.2 Hz), 4.99 (1H, m), 6.36 (1H, s), 7.42 (1H, dd, J = 4.8, 8.0 Hz), 8.11 (1H, d, J = 8.0 Hz) 8.70 (1H, d, J = 4.4 Hz), 9.00 (1H, d, J = 2.0 Hz).

Example 3:
Synthesis of 7-O-tert-butyldimethylsilyl-1,7,11-trideacetylpyripyropene A 7-O-tert-butyldimethylsilyl-7-deacetylpyripyropene A (470 mg) obtained in Example 2 ) Was dissolved in 88% aqueous methanol (40 mL), potassium carbonate (307 mg) was added, and the mixture was stirred at room temperature for 19 hours and half. The solvent was distilled off under reduced pressure, and water and ethyl acetate were added to the residue. 7-O-tert-butyldimethylsilyl-1,7,11-trideacetylpyripyropene A (65 mg) was obtained by filtering the solid substance which does not melt | dissolve. The mother liquor was extracted with ethyl acetate, and then the ethyl acetate layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 7-O-tert-butyldimethylsilyl-1,7,11-trideacetylpyripyropene A (235 mg). In addition, 300 mg (yield of 95% of the two steps from Example 2) of 7-O-tert-butyldimethylsilyl-1,7,11-trideacetylpyripyropene A was obtained.

ESI-MS: m / z 572 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 0.08 (3H, s), 0.13 (3H, s), 0.64 (3H, s), 0.90 (9H, s), 1.19 (1H, dt, J = 3.6, 12.8 Hz), 1.31 (3H, s), 1.33-1.36 (2H, m), 1.48 (1H, t, J = 12.0 Hz), 1.53 (3H, s), 1.62-1.80 (3H, m), 1.99-2.03 (1H, m), 3.16 (1H, d, J = 10.8 Hz), 3.44 (1H, d, J = 10.8 Hz), 3.56 (1H, dd, J = 4.8, 11.6 Hz), 3.76 (1H, dd, J = 5.2, 11.2 Hz), 4.86 (1H, d, J = 3.2 Hz), 6.47 (1H, s), 7.47 (1H, ddd, J = 0.8, 4.8, 8.0 Hz), 8.17 (1H, dt, J = 2.0, 8.4 Hz), 8.55 (1H, dd, J = 2.0, 4.8 Hz), 8.91 (1H, dd, J = 0.8, 2.4 Hz).

Example 4:
Synthesis of 7-O-tert-butyldimethylsilyl-1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetylpyrilopene A 7-O-tert-butyl synthesized by the method of Example 3 Dimethylsilyl-1,7,11-trideacetylpyrilopene A (57 mg) is dissolved in N, N-dimethylformamide (2 mL), pyridine (0.5 mL) is added at 0 ° C., and the mixture is stirred at the same temperature for 30 minutes. And cyclopropanecarbonyl chloride (62 mg) was added. After stirring at the same temperature for 3 hours, the reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 7-O-tert-butyldimethylsilyl-1,11-O-dicyclopropanecarbonyl-1, A crude product (87 mg) of 7,11-trideacetylpyripyropene A was obtained. This was purified by preparative thin-layer column chromatography (Merck silica gel 60F ₂₅₄ 0.5 mm, chloroform: methanol = 30: 1), and 7-O-tert-butyldimethylsilyl-1,11-O-dicyclopropane. Carbonyl-1,7,11-trideacetylpyripyropene A (67 mg, 95% yield) was obtained.

ESI-MS: m / z 708 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 0.11 (3H, s), 0.15 (3H, s), 0.85-0.88 (4H, m), 0.91 (3H, s), 0.96 (9H, s), 0.92-1.01 (4H, m), 1.25-1.36 (1H, m), 1.42 (3H, s), 1.45-1.47 (1H, m), 1.53-1.65 (5H, m), 1.58 (3H, s), 1.80-1.93 (2H, m), 2.12-2.16 (1H, m), 2.81 (1H, d, J = 2.0 Hz), 3.65 (1H, d, J = 12.0 Hz), 3.70 (1H, m), 3.91 (1H, d, J = 11.6 Hz), 4.81 (1H, dd, J = 4.8, 11.6 Hz), 4.98 (1H, m), 6.36 (1H, s), 7.41 (1H, dd, J = 4.8, 8.0 Hz), 8.10 (1H, dt, J = 2.0, 8.4 Hz), 8.69 (1H, dd, J = 1.6, 4.8 Hz), 9.00 (1H, d, J = 2.0 Hz).

Example 5:
Synthesis of 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A 7-O-tert-butyldimethylsilyl-1,11-O-di synthesized by the method of Example 4 Cyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A (100 mg) is dissolved in tetrahydrofuran (1.5 mL), and pyridine (0.6 mL), hydrogen fluoride / pyridine (0.9 mL) at 0 ° C. Was added. After stirring at the same temperature for 4 days, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A. Of crude product (92 mg) was obtained. This was purified by preparative thin-layer column chromatography (Merck Silica Gel 60F ₂₅₄ 0.5 mm, chloroform: methanol = 20: 1) to give 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetyl. Pyripyropene A (79 mg, 95% yield) was obtained.

ESI-MS: m / z 594 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 0.85-0.88 (4H, m), 0.92 (3H, s), 0.96-1.01 (4H, m), 1.35 (1H, dt, J = 4.0, 12.6 Hz), 1.42 (3H, s), 1.45-1.50 (2H, m), 1.56-1.63 (3H, m), 1.66 (3H, s), 1.79-1.93 (3H, m), 2.14 (1H, m), 2.17 (1H , d, J = 3.6 Hz), 2.85 (1H, d, J = 2.0 Hz), 3.74 (1H, d, J = 12.0 Hz), 3.78-3.82 (1H, m), 3.86 (1H, d, J = 11.6 Hz), 4.82 (1H, dd, J = 5.2, 11.6 Hz), 4.99 (1H, m), 6.52 (1H, s), 7.42 (1H, dd, J = 4.8, 8.0 Hz), 8.11 (1H, dt, J = 1.9, 8.1 Hz), 8.70 (1H, dd, J = 1.6, 4.8 Hz), 9.00 (1H, d, J = 2.0 Hz).

Example 6:
Synthesis of 7-deacetyl-7-O-tetrahydropyranylpyrpyropenpen A 7-deacetylpyripyropene A (500 mg) obtained by the method of Example 1 was dissolved in dichloromethane (10 mL), and 3,4-dihydro Pyran (372 mg) and p-toluenesulfonic acid pyridinium salt (348 mg) were added. After stirring at room temperature for 73 hours and a half, the reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give a crude product of 7-deacetyl-7-O-tetrahydropyranylpyripyropene A (742 mg). Obtained. From the measurement results of ESI-MS and ¹ H-NMR, it was confirmed that it was PR-44 described in JP-A-08-2559569.

Example 7:
Synthesis of 1,7,11-trideacetyl-7-O-tetrahydropyranyl pyripyropene A 7-deacetyl-7-O-tetrahydropyranyl pyropyropene A (742 mg) obtained in Example 6 was dissolved in 66% methanol. It melt | dissolved in aqueous solution (9 mL), potassium carbonate (511 mg) was added, and it stirred at room temperature for 4 hours. 1,7,11-Trideacetyl-7-O-tetrahydropyranylpyrilopene A (453 mg, 90% yield in two steps from Example 6) was obtained by adding water and filtering out the insoluble solid. Got.

ESI-MS: m / z 542 (M + H) ⁺ .

Example 8:
Synthesis of 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetyl-7-O-tetrahydropyranyl pyripyropene A 1,7,11-trideacetyl- synthesized by the method of Example 7 Dissolve 7-O-tetrahydropyranyl pyripyropene A (450 mg) in N, N-dimethylformamide (6 mL), add pyridine (3 mL) at 0 ° C., stir at the same temperature for 10 minutes, and cyclopropanecarbonyl chloride. (525 mg) was added. After stirring at the same temperature for 1 hour, the reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetyl-7-O. -Crude product (800 mg) of tetrahydropyranylpyripyropene A was obtained.

ESI-MS: m / z 678 (M + H) ⁺ .

Example 9:
Synthesis of 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetyl obtained in Example 8 -7-O-tetrahydropyranylpyripyropene A (800 mg) was dissolved in methanol (8 mL), and p-toluenesulfonic acid monohydrate (142 mg) was added at 0 ° C. After stirring at the same temperature for 21 hours and a half, an aqueous sodium hydrogen carbonate solution was added, methanol was distilled off under reduced pressure, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetylpyripyropene. A crude product of A (570 mg) was obtained. This was purified by silica gel chromatography (Mega Bond Elut (Varian), acetone: hexane = 3: 5), and 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A (346 mg, 2-step yield 70% from Example 8). It was in agreement with the ESI-MS data and ¹ H-NMR data of Example 5.

Example 10:
Synthesis of 1,7,11-trideacetylpyripyropene A Pyripyropene A (1 g) was dissolved in 66% aqueous methanol (15 mL), potassium carbonate (355 mg) was added, and the mixture was stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure, ethyl acetate and water were added, and crystals that were not dissolved were collected by filtration to obtain 1,7,11-trideacetylpyripyropene A (737 mg, 94% yield). From the measurement results of ESI-MS and ¹ H-NMR, it was confirmed that it was PR-3 described in JP-A No. 08-259569.

Example 11:
Synthesis of 1,7,11-trideacetyl-1,11-O-isopropylidenepyripyropene A 1,7,11- trideacetylpyripyropene A (200 mg) synthesized by the method of Example 10 was converted to N, N -Dissolved in dimethylformamide (2 mL), acetone dimethyl acetal (456 mg) and p-toluenesulfonic acid pyridinium salt (550 mg) were added. After stirring for 25 and a half hours at room temperature, the reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 1,7,11-trideacetyl-1,11-O-isopropylidene. A crude product of pyripyropene A was obtained. This was purified by preparative thin-layer column chromatography (Merck silica gel 60F ₂₅₄ 0.5 mm, chloroform: methanol = 10: 1), and 1,7,11-trideacetyl-1,11-O-isopropylidenepyripyro Pen A (171 mg, 79% yield) was obtained. From the measurement results of ESI-MS and ¹ H-NMR, it was confirmed that it was PR-16 described in JP-A-08-269065.

Example 12:
Synthesis of 7-O-tert-butyldimethylsilyl-1,7,11-trideacetyl-1,11-O-isopropylidenepyridopenpen A 1,7,11-trideacetyl- synthesized by the method of Example 11 1,11-O-isopropylidene pyripyropene A (168 mg) was dissolved in N, N-dimethylformamide (2 mL), and imidazole (92 mg) and tert-butyldimethylchlorosilane (204 mg) were added. After stirring at room temperature for 22 hours, the reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 7-O-tert-butyldimethylsilyl-1,7,11-trideacetyl-1,11- A crude product (193 mg) of O-isopropylidenepyrpyropenne A was obtained. This was purified by preparative thin-layer column chromatography (Merck silica gel 60F ₂₅₄ 0.5 mm, chloroform: methanol = 20: 1), and 7-O-tert-butyldimethylsilyl-1,7,11-trideacetyl- 1,11-O-isopropylidene pyripyropene A (187 mg, 90% yield) was obtained.

ESI-MS: m / z 612 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 0.11 (3H, s), 0.16 (3H, s), 0.96 (9H, s), 1.03 (1H, m), 1.10 (3H, s), 1.33 (1H, dt , J = 3.6, 12.8 Hz), 1.40 (3H, s), 1.43 (3H, s), 1.44 (3H, s), 1.39-1.44 (1H, m), 1.55-1.58 (2H, m), 1.58 ( 3H, s), 1.64 (1H, q, J = 12.0 Hz), 1.81 (1H, dq, J = 3.6, 12.8 Hz), 2.20 (1H, dt, J = 3.2, 12.8 Hz), 2.81 (1H, d , J = 1.6 Hz), 3.42 (1H, d, J = 10.8 Hz), 3.51 (1H, d, J = 10.4 Hz), 3.50-3.53 (1H, m), 3.72 (1H, dd, J = 4.8, 11.2 Hz), 4.97 (1H, m), 6.35 (1H, s), 7.41 (1H, dd, J = 4.8, 8.0 Hz), 8.10 (1H, dt, J = 1.6, 8.0 Hz), 8.69 (1H, dd, J = 1.6, 4.8 Hz), 9.00 (1H, d, J = 2.0 Hz).

Example 13:
7-O-tert-butyldimethylsilyl -1,7,11- tri-deacetyl pyridinium pyromellitic pen A 7-O-tert- butyldimethylsilyl was synthesized by the method of Example 12 of -1,7,11- Torideasechiru -1,11-O-isopropylidenepyridopene A (116 mg) was dissolved in tetrahydrofuran (1 mL), and 63% acetic acid (4 mL) was added at 0 ° C. After stirring at room temperature for 24 hours, an aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The chloroform layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 7-O-tert-butyldimethylsilyl-1,7,11-tride. A crude product (101 mg) of acetylpyripyropene A was obtained. This was purified by preparative thin-layer column chromatography (Merck Silica Gel 60F ₂₅₄ 0.5 mm, chloroform: methanol = 10: 1) to give 7-O-tert-butyldimethylsilyl-1,7,11-trideacetylpyridine. Piloten A (91 mg, 84% yield) was obtained.

ESI-MS: m / z 572 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 0.08 (3H, s), 0.13 (3H, s), 0.64 (3H, s), 0.90 (9H, s), 1.19 (1H, dt, J = 3.6, 12.8 Hz), 1.31 (3H, s), 1.33-1.36 (2H, m), 1.48 (1H, t, J = 12.0 Hz), 1.53 (3H, s), 1.62-1.80 (3H, m), 1.99-2.03 (1H, m), 3.16 (1H, d, J = 10.8 Hz), 3.44 (1H, d, J = 10.8 Hz), 3.56 (1H, dd, J = 4.8, 11.6 Hz), 3.76 (1H, dd, J = 5.2, 11.2 Hz), 4.86 (1H, d, J = 3.2 Hz), 6.47 (1H, s), 7.47 (1H, ddd, J = 0.8, 4.8, 8.0 Hz), 8.17 (1H, dt, J = 2.0, 8.4 Hz), 8.55 (1H, dd, J = 2.0, 4.8 Hz), 8.91 (1H, dd, J = 0.8, 2.4 Hz).

Example 14:
Synthesis of 1,11-dideacetyl-1,11-O-isopropylidenepyrpyropenpen A 1,7,11-trideacetyl-1,11-O-isopropylidenepyrpyropenpen A synthesized by the method of Example 11 ( 100 mg) was dissolved in dichloromethane (2 mL), and triethylamine (61 mg), 4-dimethylaminopyridine (7 mg), and acetic anhydride (26 mg) were added. After stirring at room temperature for 4 hours, the reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a crude product of 1,11-dideacetyl-1,11-O-isopropylidenepyridopopenen A ( 120 mg) was obtained. This was purified by preparative thin-layer column chromatography (Merck Silica Gel 60F ₂₅₄ 0.5 mm, chloroform: methanol = 20: 1) to give 1,11-dideacetyl-1,11-O-isopropylidenepyripyropene A ( 103 mg, 95% yield). From the measurement results of ESI-MS and ¹ H-NMR, it was confirmed that it was PR-43 described in JP-A-08-269065.

Example 15:
Synthesis of 1,11-dideacetylpyridopopenen A 1,11-dideacetyl-1,11-O-isopropylidenepyridopopenen A (99 mg) synthesized by the method of Example 14 was added to tetrahydrofuran (1.2 mL) and methanol. (2.4 mL) and p-toluenesulfonic acid pyridinium salt (185 mg) was added. After stirring at room temperature for 30 hours, triethylamine was added, and the solvent was distilled off under reduced pressure. Chloroform and water were added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a crude product (85 mg) of 1,11-dideacetylpyrpyropenne A. This was purified by preparative thin-layer column chromatography (Merck Silica Gel 60F ₂₅₄ 0.5 mm, chloroform: methanol = 60: 1) to give 1,11-dideacetylpyripyropene A (64 mg, yield 72%). Obtained. From the measurement results of ESI-MS and ¹ H-NMR, it was confirmed that it was PR-5 described in JP-A No. 08-259569.

Example 15a:
Synthesis of 1,11-dideacetylpyripyropene A 1,7,11-trideacetylpyrilopene A (9.67 g) was suspended in N, N-dimethylformamide (48 mL), and acetone dimethyl acetal (6. 61 g) and p-toluenesulfonic acid monohydrate (0.08 g) were added and stirred at 38-41 ° C. for 4 hours. 4-Dimethylaminopyridine (0.08 g) was added and evaporated under reduced pressure for 1 hour and a half, and then cooled to 0 ° C. Triethylamine (2.57 g) and acetic anhydride (2.37 g) were added to the solution, and the mixture was stirred at the same temperature for 16 hours. Water (96 g) was added to the reaction solution, and the pH was adjusted to 7.17 with 5% hydrochloric acid. . The precipitated pale yellow powder was filtered and washed twice with water (20 g). The obtained crude product was suspended in methanol (48 mL), 15% hydrochloric acid (4.7 g) was added, and the mixture was stirred at 25 to 27 ° C. for 2 hr. Water (33 mL) was added and insolubles were filtered, and then the pH was adjusted to 4.41 with 5% aqueous sodium hydroxide solution. Further, water (31 mL) was added, and the precipitated pale yellow powder was filtered and washed twice with 30% aqueous methanol (20 mL). It dried at 40 degreeC for 23 hours, and obtained 8.11g of 1,11-dideacetyl pyripyropene A. The measurement result of ¹ H-NMR coincided with the measurement result of the compound of Example 15.

Example 16:
Synthesis of 1,11-O-dicyclopropanecarbonyl-1,11-dideacetylpyrpyropenne A Dissolved in formamide (1.2 mL), pyridine (0.3 mL) was added at 0 ° C., stirred at the same temperature for 10 minutes, and cyclopropanecarbonyl chloride (77 mg) was added. After stirring for 1.5 hours at the same temperature, the reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give crude 1,11-O-dicyclopropanecarbonyl-1,11-dideacetylpyridopopenen A. The product (97 mg) was obtained. This was purified by preparative thin-layer column chromatography (Merck Silica Gel 60F ₂₅₄ 0.5 mm, chloroform: methanol = 20: 1) to give 1,11-O-dicyclopropanecarbonyl-1,11-dideacetylpyripyro. Pen A (73 mg, 93% yield) was obtained.

ESI-MS: m / z 636 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 0.84-0.89 (4H, m), 0.89 (3H, s), 0.90-1.06 (4H, m), 1.37 (1H, dt, J = 3.8, 13.2 Hz), 1.45 (3H, s), 1.53 (1H, d, J = 4.0 Hz), 1.55-1.67 (4H, m), 1.70 (3H, s), 1.79-1.87 (2H, m), 1.89-1.94 (2H, m ), 2.14-2.18 (1H, m), 2.16 (3H, s), 2.97 (1H, d, J = 2.0 Hz), 3.77 (2H, s), 4.81 (1H, dd, J = 4.8, 11.7 Hz) , 5.00 (1H, m), 5.02 (1H, dd, J = 5.0, 11.4 Hz), 6.46 (1H, s), 7.40 (1H, dd, J = 4.9, 8.0 Hz), 8.09 (1H, dt, J = 1.9, 8.1 Hz), 8.68 (1H, dd, J = 1.6, 4.8 Hz), 9.00 (1H, d, J = 2.0 Hz).

Example 16a:
Synthesis of 1,11-0-dicyclopropanecarbonyl-1,11-dideacetylpyripyropene A 1,11-dideacetylpyripyropene A (25.76 g) was suspended in ethyl acetate (130 mL) and pyridine was added. (15.84 g) was added and cooled to 10-15 ° C. Cyclopropanecarbonyl chloride (15.70 g) was added dropwise and stirred at 25-30 ° C. for 3 hours. The mixture was cooled again to 10 to 15 ° C., water (50 mL) was added dropwise, and the pH was adjusted to 2.59 with 5N hydrochloric acid. The organic layer obtained by liquid separation was washed successively with 5% aqueous sodium bicarbonate (50 mL) and 10% brine (50 mL). The obtained ethyl acetate solution was distilled off under reduced pressure and further replaced with methanol to adjust the liquid volume to about 130 mL. Water (130 mL) was added dropwise and the pale yellow powder deposited was filtered and washed twice with 50% aqueous methanol (40 mL). It dried at 40 degreeC for 23 hours, and obtained 30.80g of 1,11-0-dicyclopropane carbonyl- 1,11-dideacetyl pyripyropene A. The measurement result of ¹ H-NMR coincided with the measurement result of the compound of Example 16.

Example 17:
1, 11-O-di-cyclopropanecarbonyl -1,7,11- tri-deacetyl pyridinium pyromellitic pen A 1, 11-O-di-cyclopropanecarbonyl was synthesized by the method of Example 16 1,11 Jideasechiru Pyripyropene A (67 mg) was dissolved in 95% aqueous methanol (0.07 mL), and sodium carbonate (22 mg) was added at 0 ° C. After stirring at the same temperature for 4 days, acetic acid was added, methanol was distilled off under reduced pressure, and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A. Of crude product (74 mg) was obtained. This was purified by preparative thin-layer column chromatography (Merck silica gel 60F ₂₅₄ 0.5 mm, chloroform: methanol = 10: 1), and 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetyl. Pyripyropene A (47 mg, yield 76%) was obtained. It was in agreement with the ESI-MS data and ¹ H-NMR data of Example 5.

Example 17a:
Synthesis of 1,11-0-dicyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A 1,11-0-dicyclopropanecarbonyl-1,11-dideacetylpyripyropene A (30.00 g ) Was suspended in a mixture of water (20 mL) and methanol (190 mL) and cooled to 0-5 ° C. Sodium methoxide in 1M-methanol (4.49 mL) was added and stirred at the same temperature for 23 hours. 1.2% hydrochloric acid (20 mL) was added and the mixture was filtered through a 0.5 μm filter. The liquid volume was adjusted to about 90 mL by distilling off under reduced pressure. A liquid mixture of methanol / water = 2/1 (120 mL) was added to adjust the liquid volume to about 150 mL, and a liquid mixture of methanol / water = 2/1 (120 mL) was further added to adjust the liquid volume to about 180 mL. The mixture was stirred for 1 hour at room temperature, then cooled to 5 ° C. and stirred for 17 hours. The precipitated pale yellow powder was filtered and washed twice with 30% aqueous methanol (50 mL). It dried at 40 degreeC for 22 hours, and obtained 23.82g of 1,11-0-dicyclopropanecarbonyl-1,7,11-trideacetyl pyripyropene A. The measurement result of ¹ H-NMR coincided with the measurement result of the compound of Example 17.

Example 18:
Synthesis of 7-O-chloroacetyl-1,7,11-trideacetyl-1,11-O-isopropylidene pyripyropene A 1,7,11-trideacetyl-1,11 synthesized by the method of Example 11 -O-isopropylidene pyripyropene A (100 mg) was dissolved in tetrahydrofuran (2 mL), and triethylamine (61 mg) and chloroacetic anhydride (103 mg) were added. After stirring for 3.5 hours at room temperature, the reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and 7-O-chloroacetyl-1,7,11-trideacetyl-1,11-O-isopropylate was removed. A crude product (118 mg) of redenpyrilopene A was obtained. This was purified by preparative thin-layer column chromatography (Merck silica gel 60F ₂₅₄ 0.5 mm, chloroform: methanol = 20: 1), and 7-O-chloroacetyl-1,7,11-trideacetyl-1,11. -O-isopropylidenepyridopopenen A (80 mg, 70% yield) was obtained.

ESI-MS: m / z 574 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 1.11 (3H, s), 1.16 (1H, dd, J = 2.4, 12.6 Hz), 1.33-1.41 (1H, m), 1.44 (3H, s), 1.45 (3H , s), 1.52 (1H, d, J = 4.0 Hz), 1.58-1.65 (1H, m), 1.62 (3H, s), 1.70 (3H, s), 1.66-1.75 (2H, m), 1.77- 1.86 (1H, m), 2.22 (1H, m), 2.90 (1H, d, J = 2.0 Hz), 3.48 (2H, s), 3.54 (1H, dd, J = 3.6, 12.0 Hz), 4.19 (2H , d, J = 4.0 Hz), 5.00 (1H, m), 5.09 (1H, dd, J = 5.6, 11.6 Hz), 6.45 (1H, s), 7.41 (1H, dd, J = 4.8, 8.0 Hz) 8.10 (1H, dt, J = 1.6, 8.0Hz), 8.70 (1H, dd, J = 1.6, 4.8 Hz), 9.02 (1H, d, J = 1.6 Hz).

Example 19:
7-O-chloroacetyl -1,7,11- tri-deacetyl pyridinium pyro pen was synthesized by the method of Example 18 of A 7-O-chloroacetyl -1,7,11- Torideasechiru -1,11-O -Isopropylidenepyripyropene A (35 mg) was dissolved in tetrahydrofuran (0.6 mL) and methanol (1.2 mL), and p-toluenesulfonic acid pyridinium salt (61 mg) was added. After stirring at room temperature for 31 hours, the reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a crude product of 7-O-chloroacetyl-1,7,11-trideacetylpyripyropene A. (30 mg) was obtained. This was purified by preparative thin-layer column chromatography (Merck Silica Gel 60F ₂₅₄ 0.5 mm, chloroform: methanol = 10: 1), and 7-O-chloroacetyl-1,7,11-trideacetylpyripyropene A (24 mg, 74% yield) was obtained.

ESI-MS: m / z 534 (M + H) ⁺ ;
¹ H-NMR (CD ₃ OD): δ 0.74 (3H, s), 1.32 (1H, m), 1.44 (3H, s), 1.54 (2H, m), 1.69-1.75 (2H, m), 1.75 ( 3H, s), 1.79-1.86 (1H, m), 1.91-1.94 (1H, m), 2.12 (1H, m), 3.26 (1H, d, J = 11.6 Hz), 3.52 (1H, d, J = 10.8 Hz), 3.67 (1H, dd, J = 5.2, 11.6 Hz), 4.33 (2H, d, J = 2.4 Hz), 4.98 (1H, m), 5.15 (1H, dd, J = 5.2, 11.6 Hz) , 6.79 (1H, s), 7.55 (1H, dd, J = 4.8, 8.0 Hz), 8.28 (1H, dt, J = 2.4, 8.0 Hz), 8.62 (1H, dd, J = 1.6, 4.8 Hz), 9.02 (1H, d, J = 2.4 Hz).

Example 20:
Synthesis of 7-O-chloroacetyl-1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A 7-O-chloroacetyl-1,7 synthesized by the method of Example 19 , 11-Trideacetylpyripyropene A (21 mg) was dissolved in N, N-dimethylformamide (1.2 mL), and pyridine (0.3 mL) and cyclopropanecarbonyl chloride (25 mg) were added at 0 ° C. After stirring for 2.5 hours at the same temperature, the reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 7-O-chloroacetyl-1,11-O-dicyclopropanecarbonyl-1,7,11. -Crude product (37 mg) of trideacetyl pyripyropene A was obtained. This was purified by preparative thin layer column chromatography (Merck Silica Gel 60F ₂₅₄ 0.5 mm, chloroform: methanol = 30: 1) to give 7-O-chloroacetyl-1,11-O-dicyclopropanecarbonyl-1 , 7,11-Trideacetylpyripyropene A (16 mg, 58% yield) was obtained.

ESI-MS: m / z 670 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 0.85-0.90 (4H, m), 0.91 (3H, s), 0.96-1.08 (4H, m), 1.38 (1H, dt, J = 4.0, 12.6 Hz), 1.45 (3H, s), 1.54-1.67 (5H, m), 1.72 (3H, s), 1.81-1.95 (3H, m), 2.17 (1H, m), 2.89 (1H, d, J = 1.6 Hz), 3.78 (2H, s), 4.17 (2H, d, J = 2.8 Hz), 4.82 (1H, dd, J = 4.8, 11.6 Hz), 5.01 (1H, m), 5.09 (1H, dd, J = 5.2, 11.6 Hz), 6.45 (1H, s), 7.41 (1H, dd, J = 4.8, 8.0 Hz), 8.10 (1H, dt, J = 1.6, 8.0 Hz), 8.69 (1H, dd, J = 1.6, 4.8 Hz), 9.02 (1H, d, J = 1.6 Hz).

Example 21:
Synthesis of 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A 7-O-chloroacetyl-1,11-O-dicyclopropanecarbonyl synthesized by the method of Example 20 -1,7,11-trideacetylpyripyropene A (14 mg) was dissolved in 95% aqueous methanol (1.4 mL), and sodium bicarbonate (1.9 mg) was added. After stirring at room temperature for 3 hours, acetic acid was added, and methanol was distilled off under reduced pressure to obtain a crude product of 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetylpyripyropene A. It was. This was purified by preparative thin-layer column chromatography (Merck silica gel 60F ₂₅₄ 0.5 mm, chloroform: methanol = 10: 1), and 1,11-O-dicyclopropanecarbonyl-1,7,11-trideacetyl. Pyripyropene A (12 mg, 94% yield) was obtained. It was in agreement with the ESI-MS data and ¹ H-NMR data of Example 5.

Example 22:
Synthesis of 1,11-O-benzylidene-1,7,11-trideacetylpyripyropene A 1,7,11-trideacetylpyripyropene A (1.0 g) synthesized by the method of Example 10 It melt | dissolved in N-dimethylformamide (10 mL), p-toluenesulfonic acid pyridinium salt (2.75 g) and benzaldehyde dimethyl acetal (3.3 g) were added. After stirring at room temperature for 5 hours, the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give crude 1,11-O-benzylidene-1,7,11-trideacetylpyripyropene A The product was obtained. This was purified by silica gel chromatography (Mega Bond Elut (Varian), acetone: chloroform = 1: 10) to give 1,11-O-benzylidene-1,7,11-trideacetylpyripyropene A (887 mg, Yield 74%) was obtained. From the measurement results of ESI-MS and ¹ H-NMR, it was confirmed that it was PR-93 described in JP-A-08-269065.

Example 23:
Synthesis of 1,11-O-benzylidene-7-O-chloroacetyl-1,7,11-trideacetylpyripyropene A 1,11-O-benzylidene-1,7,11 synthesized by the method of Example 22 -Trideacetyl pyripyropene A (1.0 g) was dissolved in pyridine (2.5 mL) and chloroacetic anhydride (206 mg) was added at 0 ° C. After stirring at the same temperature for 1.5 hours, the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 1,11-O-benzylidene-7-O-chloroacetyl-1,7,11-tride. A crude product of acetylpyripyropene A was obtained. This was purified by silica gel chromatography (Mega Bond Elut (Varian), acetone: hexane = 1: 100) to give 1,11-O-benzylidene-7-O-chloroacetyl-1,7,11-trideacetyl. Pyripyropene A (359 mg, 72% yield) was obtained.

ESI-MS: m / z 622 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 1.19-1.22 (1H, m), 1.25 (3H, s), 1.41 (1H, m), 1.48 (3H, s), 1.53-1.56 (1H, m), 1.70 (3H, s), 1.70-1.84 (3H, m), 1.95 (1H, m), 2.27 (1H, m), 2.88 (1H, d, J = 1.6 Hz), 3.49 (1H, d, J = 10.4 Hz), 3.50-3.53 (1H, m), 3.89 (1H, d, J = 10.4 Hz), 4.20 (2H, d, J = 3.2 Hz), 5.02 (1H, m), 5.12 (1H, dd, J = 5.2, 11.6 Hz), 5.54 (1H, s), 6.46 (1H, s), 7.33-7.43 (4H, m), 7.51 (2H, dd, J = 1.6, 8.0 Hz), 8.11 (1H, dt, J = 2.0, 8.0 Hz), 8.70 (1H, dd, J = 1.6, 4.8 Hz), 9.02 (1H, d, J = 2.0 Hz).

Example 24:
Synthesis of 7-O-chloroacetyl-1,7,11-trideacetylpyripyropene A 1,11-O-benzylidene-7-O-chloroacetyl-1,7,11- synthesized by the method of Example 23 Trideacetyl pyripyropene A (10 mg) was dissolved in chloroform (1 mL) and methanol (9 mL), and 10-camphorsulfonic acid (3 mg) was added. After stirring at room temperature for 5 days, the reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a crude product of 7-O-chloroacetyl-1,7,11-trideacetylpyripyropene A. Got. This was purified by silica gel chromatography (Mega Bond Elut (Varian), acetone: chloroform = 1: 10) to give 7-O-chloroacetyl-1,7,11-trideacetylpyripyropene A (8 mg, yield). 100%). Consistent with the ESI-MS data and ¹ H-NMR data of Example 19.

Example 25:
Synthesis of 1,7,11-trideacetyl-1,11-O-p-methoxybenzylidenepyripyropene A 1,7,11-trideacetylpyrilopene A (1.0 g) synthesized by the method of Example 10 Was dissolved in N, N-dimethylformamide (22 mL), and p-toluenesulfonic acid pyridinium salt (2.76 g) and p-methoxybenzaldehyde dimethyl acetal (0.4 g) were added. After stirring at room temperature for 4 hours, the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain 1,7,11-trideacetyl-1,11-Op-methoxybenzylidenepyrpyropen. A crude product of A was obtained. This was purified by silica gel chromatography (Mega Bond Elut (Varian), acetone: chloroform = 1: 10) to obtain 1,7,11-trideacetyl-1,11-Op-methoxybenzylidenepyripyropene A. (520 mg, 41% yield) was obtained. From the measurement results of ESI-MS and ¹ H-NMR, it was confirmed that it was PR-124 described in JP-A-08-269065.

Example 26:
Synthesis of 7-O-chloroacetyl-1,7,11-trideacetyl-1,11-O-p-methoxybenzylidenepyrpyropenpen A 1,7,11-trideacetyl-1 synthesized by the method of Example 25 , 11-O-p-methoxybenzylidenepyripyropene A (100 mg) was dissolved in tetrahydrofuran (2 mL), and triethylamine (50 mg) and chloroacetic anhydride (60 mg) were added. After stirring at room temperature for 2.5 hours, the reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 7-O-chloroacetyl-1,7,11-trideacetyl-1,11-Op. -A crude product of methoxybenzylidenepyripyropene A was obtained. This was recrystallized from methanol and ethyl acetate, further purified by silica gel chromatography (Mega Bond Elut (Varian), acetone: chloroform = 1: 30), and 7-O-chloroacetyl-1,7,11- Obtained trideacetyl-1,11-Op-methoxybenzylidene pyripyropene A (83 mg, 75% yield).

ESI-MS: m / z 652 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 1.20 (1H, m), 1.24 (3H, s), 1.40 (1H, m), 1.47 (3H, s), 1.54 (1H, d, J = 3.6 Hz), 1.72 (3H, s), 1.66-1.80 (3H, m), 1.93 (1H, m), 2.26 (1H, m), 2.87 (1H, d, J = 2.0 Hz), 3.47 (1H, d, J = 10.0 Hz), 3.47-3.51 (1H, m), 3.80 (3H, s), 3.87 (1H, d, J = 10.4 Hz), 4.20 (2H, d, J = 3.2 Hz), 5.01 (1H, m) , 5.12 (1H, dd, J = 5.6, 11.6 Hz), 5.50 (1H, s), 6.46 (1H, s), 6.90 (2H, d, J = 8.8 Hz), 7.41 (1H, dd, J = 4.8 , 12.0 Hz), 7.43 (2H, d, J = 8.8 Hz), 8.10 (1H, dt, J = 2.0, 8.4 Hz), 8.70 (1H, dd, J = 2.4, 4.8 Hz), 9.02 (1H, d , J = 2.0 Hz).

Example 27:
7-O-chloroacetyl -1,7,11- tri-deacetyl pyridinium pyro pen was synthesized by the method of Example 26 of A 7-O-chloroacetyl -1,7,11- Torideasechiru -1,11-O -P-Methoxybenzylidenepyripyropene A (30 mg) was dissolved in chloroform (5 mL) and methanol (1 mL), and 10-camphorsulfonic acid (3 mg) was added. After stirring at room temperature for 5 days, the reaction solution was poured into water and extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a crude product of 7-O-chloroacetyl-1,7,11-trideacetylpyripyropene A. Got. This was purified by silica gel chromatography (Mega Bond Elut (Varian), acetone: chloroform = 1: 5) to give 7-O-chloroacetyl-1,7,11-trideacetylpyripyropene A (14 mg, yield). Yield 69%). Consistent with the ESI-MS data and ¹ H-NMR data of Example 19.

Claims (6)

Formula C:

[In the formula, R ′ represents a cyclic C _3-6 alkylcarbonyl group]
(A ₁ ) The following formula A1:

[In the formula, Ac represents an acetyl group]
The 7-position acetyl group of the compound A1 represented by formula (1) is selectively deacylated by hydrolysis using a base, and then the 7-position hydroxyl group is protected to give the following formula B1:

[Where:
Ac is as defined above,
R _1a is a —SiR ₃ R ₄ R ₅ group which may be substituted with a halogen atom (wherein R ₃ , R ₄ and R ₅ are each independently a linear or branched C _{1- 6} represents an alkyl group or a phenyl group), or represents a tetrahydropyranyl group ]
And then deacylating the acetyl groups at the 1-position and 11-position of the compound B1 with a base to give the following formula Fa:

[Wherein R _1a is as defined above]
Or (a ₂ ) Compound A1 or the following formula A4 ′:

[Wherein, A ₁ ′, A ₇ ′ and A ₁₁ ′ may be the same or different and each represents an acetyl group or a propionyl group, provided that A ₁ ′, A ₇ ′ and A ₁₁ ′ are acetyl groups at the same time. Does not represent]
The acyl groups at the 1-position, 7-position and 11-position of the compound A4 ′ represented by the following are deacylated by hydrolysis with a base, and then the hydroxyl groups at the 1-position and the 11-position are protected, Formula D:

[Wherein _two R ₂ , taken together, have the following formulas D-1, D-2, D-3 and D-4:

Wherein Y ₁ represents a hydrogen atom or a C _1-4 alkyl group, X may be the same or different, and represents a hydrogen atom, a C _1-4 alkoxy group or a nitro group, and n is 0 to 5 Represents a group selected from
Then, by protecting the hydroxyl group at the 7-position of compound D, the following formula E:

[Where:
R _1b is an acetyl group, a chloroacetyl group, or a —SiR ₃ R ₄ R ₅ group optionally substituted with a halogen atom (wherein R ₃ , R ₄ and R ₅ are each independently a straight chain or A branched C _1-6 alkyl group or a phenyl group), or a tetrahydropyranyl group ,
R ₂ is as defined above]
In addition, by deprotecting the 1-position and 11-position protecting groups in Compound E, the following formula Fb:

[Wherein R _1b is as defined above]
And (b) acylating the 1-position and 11-position hydroxyl groups in the compound Fa or Fb with an acylating agent corresponding to the target R ′, to obtain a compound Fb represented by the following formula B2a or B2b :

[In the formula, R _1a , R _1b and R ′ are as defined above] After obtaining compound B2a or compound B2b, the protecting group at position 7 of compound B2a or compound B2b is deprotected. A method comprising the step of: R _1b may be substituted with an acetyl group, a chloroacetyl group, or a halogen atom, -SiR ₃ R ₄ R ₅ group (wherein R ₃ , R ₄ and R ₅ are each independently a straight chain Or a branched C _1-6 alkyl group or a phenyl group). Two R ₂ , taken together, can be represented by the following formula D-1 or D-2:

Wherein Y ₁ represents a hydrogen atom or a C _1-4 alkyl group, X may be the same or different, and represents a hydrogen atom, a C _1-4 alkoxy group or a nitro group, and n is 0 to 5 The method according to claim 1, which represents Formula C:

[Wherein R ′ represents a cyclic C _3-6 alkylcarbonyl group]
A compound C represented by the formula:
Formula Fb:

[Where:
R _1b is an acetyl group, a chloroacetyl group, or a —SiR ₃ R ₄ R ₅ group optionally substituted with a halogen atom (wherein R ₃ , R ₄ and R ₅ are each independently a straight chain or A branched C _1-6 alkyl group or a phenyl group), or a tetrahydropyranyl group ]
In the compound Fb represented by formula (1), the hydroxyl groups at the 1-position and the 11-position are acylated with an acylating agent corresponding to R ′ to give the following formula B2b:

[Wherein R _1b and R ′ are as defined above]
And then deprotecting the protecting group at the 7-position of compound B2b. Formula C:

[In the formula, R ′ represents a cyclic C _3-6 alkylcarbonyl group]
Formula A4:

[Wherein A ₁ , A ₇ and A ₁₁ may be the same or different and each represents an acetyl group or a propionyl group]
The acyl groups at the 1-position, 7-position and 11-position of the compound A4 represented by the formula (1) are deacylated by hydrolysis with a base, and then the hydroxyl groups at the 1-position and the 11-position are protected, D:

[Wherein _two R ₂ , taken together, have the following formulas D-1, D-2, D-3 and D-4:

Wherein Y ₁ represents a hydrogen atom or a C _1-4 alkyl group, X may be the same or different, and represents a hydrogen atom, a C _1-4 alkoxy group or a nitro group, and n is 0 to 5 Represents a group selected from
Then, by protecting the hydroxyl group at the 7-position of compound D, the following formula E:

[Where:
R _1b is an acetyl group, a chloroacetyl group, or a —SiR ₃ R ₄ R ₅ group optionally substituted with a halogen atom (wherein R ₃ , R ₄ and R ₅ are each independently a straight chain or A branched C _1-6 alkyl group or a phenyl group), or a tetrahydropyranyl group ,
R ₂ is as defined above]
In addition, by deprotecting the 1-position and 11-position protecting groups in Compound E, the following formula Fb:

[Wherein R _1b is as defined above]
And then acylating the hydroxyl groups at the 1-position and the 11-position in the compound Fb with an acylating agent corresponding to R ′:

[Wherein R _1b and R ′ are as defined above]
And then deprotecting the protecting group at the 7-position of compound B2b. Compound represented by the following formula B2b:

[Where:
R _1b is an acetyl group, a chloroacetyl group, or a —SiR ₃ R ₄ R ₅ group optionally substituted with a halogen atom (wherein R ₃ , R ₄ and R ₅ are each independently a straight chain or A branched C _1-6 alkyl group or a phenyl group), or a tetrahydropyranyl group ,
R ′ is a cyclic C _3-6 alkylcarbonyl group].